Treatment of HIV infected individuals is one of the most pressing biomedical problems of recent times. A promising new therapy has emerged as an important method for preventing or inhibiting the rapid proliferation of the virus in human tissue. HIV protease inhibitors block a key enzymatic pathway in the virus resulting in substantially decreased viral loads, which slows the steady decay of the immune system and its resulting deleterious effects on human health. The HIV protease inhibitor nelfinavir mesylate, having the following formula:
has been shown to be an effective treatment for HIV infected individuals. Nelfinavir mesylate is disclosed in U.S. Pat. No. 5,484,926, which issued Jan. 16, 1996. This patent, in its entirety, is incorporated herein by reference.
Prior to the present invention, the stereochemistry of nelfinavir mesylate products and intermediates prepared by conventional processes was determined by the stereochemistry of the starting materials. Thus, different stereoisomers of nelfinavir mesylate or its free base could only be prepared by the use of specific enantiomeric starting materials. The present invention provides a versatile and useful synthetic route for the preparation of nelfinavir whereby key stereocenters are established at a relatively late stage in the synthesis of the 1,2-dihydroxy-3-amino-butane substituent.
HIV-Protease inhibitors prepared by use of cyclic sulfates are discussed, for example, in U.S. Pat. No. 5,705,647. Asymmetric dihydroxylation, utilized in the present invention to make nelfinavir mesylate intermediates, is discussed generally in WO 93/07142 and in Reetz et al., Asymmetric Dihydroxylation of Chiral γ-Amino α, β-Unsaturated Esters: Turning the Mismatched into the Matched Case via Protective Group Tuning, Tetrahedron Letters Vol. 37 9293–9296 (1996).
Other background processes related to the invention are found in U.S. Pat. No. 5,587,481. Processes for producing amide derivatives useful as intermediates in the synthesis of nelfinavir mesylate are found in WO 97/11937 and WO 97/11938. These references are incorporated herein by reference.